What causes familial Mediterranean fever (FMF)?

Updated: Apr 07, 2020
  • Author: John O Meyerhoff, MD; Chief Editor: Herbert S Diamond, MD  more...
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FMF is a recessive genetic disease associated with missense and nonsense mutations in the MEFV gene, which is located on the short arm of chromosome 16. This gene codes for the protein known as pyrin or marenostrin.

More than 310 sequence variants in the MEFV gene have been identified, although not all not associated with a disease phenotype. [6] Most of the pathogenic mutations are in exon 10 of the gene between amino acids 680 and 761. One mutation, in exon 1 at amino acid 148, may represent as many as one quarter of the known mutations. Although certain mutations are more common in particular ethnic groups, patients usually inherit different mutations from each parent.

Homozygotes for M694V (valine for methionine at position 694) may experience more severe disease and may be more likely to develop amyloidosis. Patients with V726A (alanine for valine at position 726) may be at a lower risk of developing amyloidosis, although one study suggests that the combination of V726A and E148Q may be particularly amyloidogenic. [8]

Other genes may be involved in FMF. This possibility is supported by patients who meet criteria for FMF without identifiable mutations in MEFV and who have clinical manifestations that are indistinguishable from patients with MEFV mutations.

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